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US6303141B1 - Transdermally administrable medicament with ACE inhibitors - Google Patents

Transdermally administrable medicament with ACE inhibitors Download PDF

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Publication number
US6303141B1
US6303141B1 US09/407,348 US40734899A US6303141B1 US 6303141 B1 US6303141 B1 US 6303141B1 US 40734899 A US40734899 A US 40734899A US 6303141 B1 US6303141 B1 US 6303141B1
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United States
Prior art keywords
delivery system
drug delivery
transdermal drug
matrix
layer
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Expired - Lifetime
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US09/407,348
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English (en)
Inventor
Wilfried Fischer
Karin Klokkers
Anna Sendl-Lang
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Hexal AG
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Hexal AG
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/401—Proline; Derivatives thereof, e.g. captopril
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/55—Protease inhibitors
    • A61K38/556—Angiotensin converting enzyme inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7069—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained otherwise than by reactions only involving carbon to carbon unsaturated bonds, e.g. polysiloxane, polyesters, polyurethane, polyethylene oxide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • ACE inhibitors angiotensin-converting enzyme inhibitors
  • captopril The first substance of the ACE inhibitor class, captopril, is a very hydrophilic substance which is active in unmodified form.
  • the oral bioavailability of captopril is approximately 70%.
  • More recent ACE inhibitors, such as enalapril, are metabolized from their precursor during passage through the liver into the active component enalaprilate, that is to say the acid form.
  • the ACE inhibitors ramipril, cilacapril, trandolapril, benazepril or fosinopril are lipophilic prodrugs of the actual active form of the dicarboxylic acid.
  • the substance becomes more lipophilic and thereby more favourable for oral absorption.
  • the oral bioavailability of these prodrugs is always lower than that of captopril. It is, for example, 28% for benazepril and about 40 to 60% for trandolapril.
  • WO-A1-9 323 019 has already disclosed a transdermal reservoir system containing an ACE inhibitor and
  • Transdermal systems containing an ACE inhibitor are furthermore described in EP-A2-0 439 430 (reservoir TTS) and EP-A2-0 468 875 (matrix TTS), according to EP-A2-0 468 875 silicone elastomers being used as matrix material.
  • the object of the present invention is to provide a system for the transdermal supply of ACE inhibitors, in particular of ramipril, trandolapril and/or their therapeutically active salts, which is improved compared with the prior art.
  • a transdermal system having a matrix based on polyisobutylene or butyl rubber and containing at least one ACE inhibitor is provided.
  • lipophilic ACE inhibitors or their active forms which can only permeate the human skin with difficulty, can penetrate the skin easily with the aid of a transdermally administrable medicament having a polyisobutylene matrix or butyl rubber matrix and produce a reliable, continuous blood level.
  • a release rate of the active compound from, for example, a polymer matrix, of 0.01 to 0.1 mg of active compound/cm 2 of 24 h and, in particular, 0.025 to 0.050 mg of active compound/cm 2 of 24 h can be achieved, such that a transdermal system according to the invention offers a plasma concentration of active compound in a therapeutically active amount.
  • a transdermal system according to the invention offers a plasma concentration of active compound in a therapeutically active amount.
  • a therapeutically active concentration in the blood of more than approximately 0.5 ng/ml can be achieved.
  • the ACE inhibitor in the transdermal system according to the invention, can be present in a concentration of at least 5% by weight and in particular in a concentration of 10 to 20% by weight (based on the matrix).
  • the ACE inhibitor can be employed here as a prodrug or as an active form.
  • ACE inhibitors examples include ramipril, trandolapril and/or their active forms (acid forms) and also their therapeutically active salts.
  • the transdermal system according to the invention can include a permeation promoter, for example 2-octyldodecanol (Eutanol G).
  • a permeation promoter for example 2-octyldodecanol (Eutanol G).
  • transdermal systems can be used, for example membrane- or matrix-controlled systems.
  • the transdermal system according to the invention can be a patch having a reservoir (patch of the reservoir type).
  • a patch of this type having a reservoir can be characterized by
  • the layer-like element having a hollow space can be formed by the covering layer and the membrane.
  • the microporous or semi-permeable membrane can consist of an inert polymer, for example polypropylene, polyvinyl acetate or silicone.
  • the reservoir can thus be formed, for example by a hollow space or in another manner.
  • the reservoir is in this case filled with the active compound/mixture of the auxiliaries.
  • the active compound with the auxiliaries permeates (through the membrane provided if appropriate) through the covering layer into the skin.
  • a membrane depending on the pore width, it can have an action controlling the release of the active compound or alternatively no influence on the release of active compound from the system.
  • the reservoir is provided by an open-pore foam, a closed-pore foam, a fabric-like layer or a web-like layer, the active compound/mixture of the auxiliaries are present in absorbed or finely divided form.
  • a microporous or semi-permeable membrane can be absent, and the layer forming the reservoir can be self-adhesive or (if that is not the case) can carry a self-adhesive layer (adhesive layer).
  • the transdermal system according to the invention can be characterized by
  • the matrix used according to the invention can be a self-adhesive polyisobutylene adhesive.
  • TTS transdermal therapeutic system
  • Matrix Polyisobutylene adhesive (MA24 from Adhesive Research Inc., Glen Rock, Pennsylvania, USA) Covering film: Polyester film (Hostaphan RN 19) Tear-off film: Polyester film (Gelroflex PET 75 ⁇ m 1-S) or coated paper film (Gelrolease 603/100 DRS) Matrix constituents: Trandolapril 10% by weight Eutanol G 5% by weight Polyisobutylene adhesive 85% by weight (Dry matter)
  • a silicone adhesive (BIO PSA X7 4302) is used instead of a polyisobutylene adhesive.
  • Example 1 shows that the active compound delivery in the system according to the invention remains constant over a period of 20 days, while it falls drastically in Comparison Example 1.
  • trandolapril capsule
  • the pharmacokinetic behaviour for TTS administration was tested on 6 healthy subjects.
  • the TTS were administered over a period of 7 days (1 TTS for 4 days, then 1 TTS for 3 days) and, in comparison, 1 capsule of 2 mg of trandolapril was administered daily for 7 days.
  • Blood samples were taken after the following times: ⁇ 0.5; 0; 2; 4; 6; 8; 10; 12; 24; 48; 72; 96; 98; 100; 102; 104; 106; 108; 120; 132; 144; 156; 168 h after administration.
  • the pharmacokinetic results show that the TTS has a fundamentally different blood level profile than the capsules.
  • a blood level which is constant over the respective administration period of 3 or 4 days is achieved, which is therapeutically also desirable.
  • the blood concentration rises rapidly, in fact about 5 ng/ml is achieved within 2 h. Elimination takes place with a half-life of about 24 h.
  • the blood level course after TTS administration is more uniform.
  • a uniform slight rise in the blood level of about 0.3 ng/ml after 6 h to about 1 ng/ml after 96 h is to be observed.
  • the blood levels in the second administration period only rise insignificantly (FIG. 1 ).
  • the blood level profile after administration of the TTS comes very close to the therapeutic ideal of constant blood levels during treatment.
  • Undesired blood level peaks which can be associated with undesired side-effects such as sudden blood pressure drop, are safely avoided.
  • Active compound Permeation Skin trandolapril promoter Day from permeation Diss.
  • E 4 10 10 Ciol V 13 0.044 none

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Dermatology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Vascular Medicine (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
US09/407,348 1995-03-31 1999-09-29 Transdermally administrable medicament with ACE inhibitors Expired - Lifetime US6303141B1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19512181A DE19512181C2 (de) 1995-03-31 1995-03-31 Transdermales System mit Ramipril und/oder Trandolapril als ACE-Hemmer
DE19512181 1995-03-31

Related Parent Applications (2)

Application Number Title Priority Date Filing Date
PCT/EP1996/001402 Continuation WO1996029999A1 (de) 1995-03-31 1996-03-29 Transdermal applizierbares arzneimittel mit ace-hemmern
US08930684 Continuation 1997-09-30

Publications (1)

Publication Number Publication Date
US6303141B1 true US6303141B1 (en) 2001-10-16

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US09/407,348 Expired - Lifetime US6303141B1 (en) 1995-03-31 1999-09-29 Transdermally administrable medicament with ACE inhibitors

Country Status (19)

Country Link
US (1) US6303141B1 (de)
EP (1) EP0817622B1 (de)
JP (1) JP3924008B2 (de)
AT (1) ATE209482T1 (de)
AU (1) AU700418B2 (de)
BR (1) BR9607872A (de)
CA (1) CA2216278A1 (de)
CZ (1) CZ287373B6 (de)
DE (2) DE19512181C2 (de)
DK (1) DK0817622T3 (de)
ES (1) ES2167558T3 (de)
HU (1) HUP9801989A3 (de)
NO (1) NO974508L (de)
NZ (1) NZ306429A (de)
PL (1) PL322576A1 (de)
PT (1) PT817622E (de)
SK (1) SK125897A3 (de)
WO (1) WO1996029999A1 (de)
ZA (1) ZA962592B (de)

Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020048596A1 (en) * 1994-12-30 2002-04-25 Gregor Cevc Preparation for the transport of an active substance across barriers
US20030099694A1 (en) * 1999-07-05 2003-05-29 Gregor Cevc Method for the improvement of transport across adaptable semi-permeable barriers
US20030152615A1 (en) * 2001-06-18 2003-08-14 Noven Pharmaceuticals, Inc. Enhanced drug delivery in transdermal systems
US20040052835A1 (en) * 2000-07-12 2004-03-18 Karin Klokkers Matrix controlled transdermal system for stabile derivatives of ace inhibitors
US20040071767A1 (en) * 2002-10-11 2004-04-15 Gregor Cevc NSAID formulations, based on highly adaptable aggregates, for improved transport through barriers and topical drug delivery
US20040086552A1 (en) * 2000-07-12 2004-05-06 Karin Klokkers Transdermal therapeutic system for highly dispersed silicon dioxide
US6805878B2 (en) 2001-09-13 2004-10-19 Noven Pharmaceuticals, Inc. Transdermal administration of ACE inhibitors
US20070237817A1 (en) * 2006-04-05 2007-10-11 Azad Pharmaceutical Ingredients Ag Polymorphic and pseudopolymorphic forms of trandolaprilat, pharmaceutical compositions and methods for production and use
US20080095722A1 (en) * 2004-11-12 2008-04-24 Idea Ag Extended Surface Aggregates in the Treatment of Skin Conditions
US20090169603A1 (en) * 2005-12-13 2009-07-02 Nitto Denko Corporation Adhesive Pharmaceutical Preparation
US20090169604A1 (en) * 2005-12-13 2009-07-02 Nitto Denko Corporation Adhesive Pharmaceutical Preparation Containing Bisoprolol
US20090291126A1 (en) * 2005-09-09 2009-11-26 Nitto Denko Corporation Adhesive pharmaceutical preparation containing bisoprolol
US7867480B1 (en) 1999-01-27 2011-01-11 Gregor Cevc Non-invasive vaccination through the skin
US7927622B1 (en) 1999-01-27 2011-04-19 Gregor Cevc Methods of transnasal transport/immunization with highly adaptable carriers
US8703178B2 (en) 2007-03-08 2014-04-22 Nitto Denko Corporation Percutaneous administration device of bisoprolol
US20140369949A1 (en) * 2005-03-24 2014-12-18 Kipax Ab Cosmetic Treatment with Nitric Oxide, Device for Performing Said Treatment and Manufacturing Method Therefor
US9427605B2 (en) 2005-03-24 2016-08-30 Novan, Inc. Cosmetic treatment with nitric oxide, device for performing said treatment and manufacturing method therefor
US9855211B2 (en) 2013-02-28 2018-01-02 Novan, Inc. Topical compositions and methods of using the same
US10206947B2 (en) 2013-08-08 2019-02-19 Novan, Inc. Topical compositions and methods of using the same
US10226483B2 (en) 2013-08-08 2019-03-12 Novan, Inc. Topical compositions and methods of using the same
US10265334B2 (en) 2011-07-05 2019-04-23 Novan, Inc. Anhydrous compositions
US10912743B2 (en) 2016-03-02 2021-02-09 Novan, Inc. Compositions for treating inflammation and methods of treating the same
US11166980B2 (en) 2016-04-13 2021-11-09 Novan, Inc. Compositions, systems, kits, and methods for treating an infection

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19820151A1 (de) * 1998-05-06 1999-11-11 Hexal Ag Transdermales therapeutisches System zur Anwendung von Candesartan
PL193824B1 (pl) 1998-12-23 2007-03-30 Idea Ag Preparat zawierający środki penetrujące, sposób wytwarzania preparatu zawierającego środki penetrujące oraz zastosowanie preparatu do wytwarzania leku
DE102005058166A1 (de) 2005-12-05 2007-06-06 Hexal Ag Matrixkontrolliertes transdermales System mit Amin-Salzen der ACE-Hemmer-Dicarbonsäuren

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NZ239074A (en) 1990-07-23 1992-10-28 Adir Self-sticking matrix system for sustained transcutaneous release of piribedil
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US5269875A (en) 1989-10-05 1993-12-14 Shin-Etsu Handotai Company, Limited Method of adjusting concentration of oxygen in silicon single crystal and apparatus for use in the method
US5464387A (en) * 1991-07-24 1995-11-07 Alza Corporation Transdermal delivery device
US5656286A (en) * 1988-03-04 1997-08-12 Noven Pharmaceuticals, Inc. Solubility parameter based drug delivery system and method for altering drug saturation concentration

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US5256687A (en) * 1985-09-09 1993-10-26 Hoechst Aktiengesellschaft Pharmaceutical composition for the treatment of high blood pressure
US5656286A (en) * 1988-03-04 1997-08-12 Noven Pharmaceuticals, Inc. Solubility parameter based drug delivery system and method for altering drug saturation concentration
US5269875A (en) 1989-10-05 1993-12-14 Shin-Etsu Handotai Company, Limited Method of adjusting concentration of oxygen in silicon single crystal and apparatus for use in the method
US5073539A (en) 1990-01-22 1991-12-17 Ciba-Geigy Corporation Transdermal administration of zwitterionic drugs
US5176916A (en) 1990-04-18 1993-01-05 Nitto Electric Industrial Co., Ltd. Medical adhesives
NZ239074A (en) 1990-07-23 1992-10-28 Adir Self-sticking matrix system for sustained transcutaneous release of piribedil
US5464387A (en) * 1991-07-24 1995-11-07 Alza Corporation Transdermal delivery device
WO1993023019A1 (en) 1992-05-11 1993-11-25 Sri International Transdermal drug delivery systems and related compositions and methods of use

Cited By (53)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020048596A1 (en) * 1994-12-30 2002-04-25 Gregor Cevc Preparation for the transport of an active substance across barriers
US7927622B1 (en) 1999-01-27 2011-04-19 Gregor Cevc Methods of transnasal transport/immunization with highly adaptable carriers
US7867480B1 (en) 1999-01-27 2011-01-11 Gregor Cevc Non-invasive vaccination through the skin
US20050123897A1 (en) * 1999-07-05 2005-06-09 Idea Ag Method for the improvement of transport across adaptable semi-permeable barriers
US20030099694A1 (en) * 1999-07-05 2003-05-29 Gregor Cevc Method for the improvement of transport across adaptable semi-permeable barriers
US7591949B2 (en) 1999-07-05 2009-09-22 Idea Ag Method for the improvement of transport across adaptable semi-permeable barriers
US7459171B2 (en) 1999-07-05 2008-12-02 Idea Ag Method for the improvement of transport across adaptable semi-permeable barriers
AU2007201226B2 (en) * 2000-07-12 2010-04-22 Hexal Ag Matrix-controlled transdermal system for stable derivatives of ACE inhibitors
US20040052835A1 (en) * 2000-07-12 2004-03-18 Karin Klokkers Matrix controlled transdermal system for stabile derivatives of ace inhibitors
US20040086552A1 (en) * 2000-07-12 2004-05-06 Karin Klokkers Transdermal therapeutic system for highly dispersed silicon dioxide
US20080167365A1 (en) * 2001-06-18 2008-07-10 Noven Pharmaceuticals, Inc. Enhanced drug delivery in transdermal systems
US20080167280A1 (en) * 2001-06-18 2008-07-10 Noven Pharmaceuticals, Inc. Enhanced drug delivery in transdermal systems
EP1406633A4 (de) * 2001-06-18 2006-08-16 Noven Pharma Verbesserte arzneimittelabgabe in transdermalen systemen
US20030152615A1 (en) * 2001-06-18 2003-08-14 Noven Pharmaceuticals, Inc. Enhanced drug delivery in transdermal systems
US7879831B2 (en) 2001-06-18 2011-02-01 Noven Pharmaceuticals, Inc. Enhanced drug delivery in transdermal systems
US20030152613A1 (en) * 2001-06-18 2003-08-14 Noven Pharmaceuticals, Inc. Enhanced drug delivery in transdermal systems
US8025898B2 (en) * 2001-06-18 2011-09-27 Noven Pharmaceuticals, Inc. Enhanced drug delivery in transdermal systems
US8110565B2 (en) 2001-06-18 2012-02-07 Noven Pharmaceuticals, Inc. Enhanced drug delivery in transdermal systems
US7456159B2 (en) 2001-06-18 2008-11-25 Noven Pharmaceuticals, Inc. Enhanced drug delivery in transdermal systems
US20030232073A1 (en) * 2001-06-18 2003-12-18 Noven Pharmaceuticals, Inc. Enhanced drug delivery in transdermal systems
US7867986B2 (en) 2001-06-18 2011-01-11 Noven Pharmaceuticals, Inc. Enhanced drug delivery in transdermal systems
US20030152614A1 (en) * 2001-06-18 2003-08-14 Noven Pharmaceuticals, Inc. Enhanced drug delivery in transdermal systems
US7846916B2 (en) 2001-06-18 2010-12-07 Noven Pharamaceticals, Inc. Enhanced drug delivery in transdermal systems
US20050100589A1 (en) * 2001-09-13 2005-05-12 Noven Pharmaceuticals, Inc. Transdermal administration of ace inhibitors
US6805878B2 (en) 2001-09-13 2004-10-19 Noven Pharmaceuticals, Inc. Transdermal administration of ACE inhibitors
US20090042989A1 (en) * 2002-10-11 2009-02-12 Idea Ag Nsaid formulations, based on highly adaptable aggregates, for improved transport through barriers and topical drug delivery
US20040071767A1 (en) * 2002-10-11 2004-04-15 Gregor Cevc NSAID formulations, based on highly adaptable aggregates, for improved transport through barriers and topical drug delivery
US20090060989A1 (en) * 2002-10-11 2009-03-05 Idea Ag Nsaid formulations, based on highly adaptable aggregates, for improved transport through barriers and topical drug delivery
US20090060990A1 (en) * 2002-10-11 2009-03-05 Idea Ag Nsaid formulations, based on highly adaptable aggregates, for improved transport through barriers and topical drug delivery
US7473432B2 (en) 2002-10-11 2009-01-06 Idea Ag NSAID formulations, based on highly adaptable aggregates, for improved transport through barriers and topical drug delivery
US20070031483A1 (en) * 2002-10-11 2007-02-08 Gregor Cevc Aggregates with increased deformability, comprising at least three amphipats, for improved transport through semi-permeable barriers and for the non-invasive drug application in vivo, especially through the skin
US20080095722A1 (en) * 2004-11-12 2008-04-24 Idea Ag Extended Surface Aggregates in the Treatment of Skin Conditions
US20140369949A1 (en) * 2005-03-24 2014-12-18 Kipax Ab Cosmetic Treatment with Nitric Oxide, Device for Performing Said Treatment and Manufacturing Method Therefor
US9427605B2 (en) 2005-03-24 2016-08-30 Novan, Inc. Cosmetic treatment with nitric oxide, device for performing said treatment and manufacturing method therefor
US20090291126A1 (en) * 2005-09-09 2009-11-26 Nitto Denko Corporation Adhesive pharmaceutical preparation containing bisoprolol
US8808731B2 (en) 2005-09-09 2014-08-19 Nitto Denko Corporation Adhesive pharmaceutical preparation containing bisoprolol
US20090169604A1 (en) * 2005-12-13 2009-07-02 Nitto Denko Corporation Adhesive Pharmaceutical Preparation Containing Bisoprolol
US8298572B2 (en) 2005-12-13 2012-10-30 Nitto Denko Corporation Adhesive pharmaceutical preparation containing bisoprolol
US20090169603A1 (en) * 2005-12-13 2009-07-02 Nitto Denko Corporation Adhesive Pharmaceutical Preparation
US7943655B2 (en) 2006-04-05 2011-05-17 Universitat Zurich Polymorphic and pseudopolymorphic forms of trandolaprilat, pharmaceutical compositions and methods for production and use
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DE19512181C2 (de) 2003-11-06
BR9607872A (pt) 1999-11-30
EP0817622A1 (de) 1998-01-14
HUP9801989A2 (hu) 1999-02-01
NO974508L (no) 1997-10-27
ES2167558T3 (es) 2002-05-16
PT817622E (pt) 2002-05-31
ATE209482T1 (de) 2001-12-15
CA2216278A1 (en) 1996-10-03
DE59608323D1 (de) 2002-01-10
NZ306429A (en) 2000-07-28
AU5498296A (en) 1996-10-16
DK0817622T3 (da) 2002-03-25
SK125897A3 (en) 1998-02-04
CZ287373B6 (en) 2000-11-15
CZ302897A3 (cs) 1998-02-18
PL322576A1 (en) 1998-02-02
MX9707507A (es) 1997-11-29
DE19512181A1 (de) 1996-10-02
WO1996029999A1 (de) 1996-10-03
JPH11502827A (ja) 1999-03-09
JP3924008B2 (ja) 2007-06-06
HUP9801989A3 (en) 2000-06-28
NO974508D0 (no) 1997-09-29
ZA962592B (en) 1997-10-01
EP0817622B1 (de) 2001-11-28
AU700418B2 (en) 1999-01-07

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